Discordant expression of perforin and granzyme A in total and HIV-specific CD8 T lymphocytes of HIV infected children and adolescents

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Abstract
Perforin and granzyme are cytotoxic effector molecules that are believed to play essential roles in cytotoxic T cell (CTL) activity. We tested the hypothesis that dysregulation of these effector molecules contributes to defects of CD8 antiviral immune responses in pediatric subjects in chronic stages of perinatal HIV infection. Studies of CD8 T cells were conducted in 33 treatment experienced HIV+ patients (median age, 10.6 years) and in 14 age-matched healthy controls. CD8 T cells specific for HIV Gag and Pol peptides were identified in HLA-A2+ patients by tetramer binding assays. HIV-specific and total CD8 T cells were examined for perforin, granzyme and expression of CD27, a marker that is lost in terminally differentiated cells. Three populations of CD8 T cells were identified: granzyme+ perforin+; granzyme+ perforin- and cells negative for both perforin and granzyme. In HIV infected patients, granzyme+ cells were increased in total CD8 T cells (39% versus 13% in controls) and were highest in HIV Gag-specific CD8 cells (42%). Perforin+ CD8 T cells were approximately fivefold fewer than granzyme+ CD8 T cells and were enriched in CD27 negative cells. Most HIV-specific CD8 cells were CD27+. Granzyme expression in CD8 T cells correlated negatively with CD4 percentage and positively with virus load. A disproportionate and generalized increase in CD27+, granzyme+, CD8 T cells is a hallmark of established pediatric HIV infection. These findings support the concept of skewed maturation, with failure of CD8 T cells to mature into perforin-enriched, CD27-negative, effector cells.

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